The objective of this project is to combine the biologic response modifying drugs, 13-cis-retinoic acid an interferon alfa-2a, with hyperfractionated radiotherapy in an effort to improve the treatment outcome of patients with locally advanced head and neck cancer. An estimated 29,600 individuals will develop head and neck cancer in the United States in 1994. Approximately 7,925 (27%) will die from the disease. Radiation therapy is used as the primary treatment for patients with cancers of the head and neck that cannot be surgically removed without undue morbidity. Potential surgical morbidity would include disfigurement and loss of voice or intelligible speech depending on the site in which the tumor arose. Because many of these tumors are large and locally advanced, the treatment outcome is often poor. Fewer than 30% of such patients are cured with conventional radiation treatment The use of hyperfractionated radiation (multiple daily radiation treatments) has improved the local control of advanced head and neck cancer without any concomitant increase in normal tissue injury. In these patients, there was a trend towards improvement in survival but this was not significant. Recently, 13-cis-retinoic acid and interferon alfa-2a have been combined with radiation therapy in patients with large cancers of the uterine cervix with high response rates. Alpha interferon and retinoic acid enhance radiation cytotoxicity. We have obtained preliminary data to suggest that the combination of retinoic acid and interferon alpha enhance the cytotoxicity of radiation against cell lines in tissue culture. In the initial phase of this proposed project, a phase I trial would determine the maximum tolerated doses of 13-cis-retinoic acid and interferon alpha that could be combined with hyperfractionated radiation therapy in patients with locally advanced and neck cancer. If these agents can be successfully combined in the Phase I trial, a phase ll trial of hyperfractionated radiation with these agents at the maximum tolerated dose would be conducted in the same patient population. If there is sufficient evidence of promising activity of this regimen, a randomized, phase III trial of the regimen compared to hyperfractionated radiation would be initiated through the cooperative group mechanism. Accompanying the clinical trial would be supportive basic laboratory projects focused on changes in radiation sensitivity induced by interferon-alfa and cis-retinoic acid. As molecular biologic changes in head and neck cancers are being studied in a parallel study, an attempt will be made to correlate responses to treatment in the clinical trial(s) with any identifiable genetic changes in the tumors.